Process for measuring blood platelet aggregation or blood coagulation

ABSTRACT

A process and device are disclosed for measuring blood platelet aggregation or blood coagulation. The blood flows through an opening in a part and the occlusion of the opening is measured. The pressure fall (ΔP) formed during occlusion of the opening is measured at predetermined time intervals (dt) and the volume flow (I) is changed to correspond to a predetermined function which simulates the flow resistance (R v ) of a capillary upstream of the opening. Alternatively, the pressure (ΔP) is kept constant during the predetermined time intervals (dt) and afterwards, when the volume flow (I) has diminished by a certain value, the pressure is adjusted until it corresponds to the function.

The invention relates to a process for the measurement of theaggregation of blood platelets or the coagulation of blood according tothe preamble of patent claim 1 and to a device for carrying out thisprocess according to the preamble of patent claim 12.

The DE 35 41 057 C2 discloses such a process, in which blood is suckedinto a capillary with the aid of a piston located in a cylinder, whichis connected to the capillary and in which the actual pressure thatprevails in the space between the piston and the aspirated blood ismeasured. This actual pressure is maintained at a desired value bymoving the piston as a function of the difference between the actualpressure and a desired value. As a measure for the aggregation or thecoagulation, the quantity of blood flow in the capillary is determinedby detecting the movement of the piston.

One problem with such a process is the fact that the capillaries to beused are extremely difficult to produce, because the flow resistance ofthe capillary is a function of the fourth power of the radius of thecapillary.

This is of the magnitude of 100 μm. This means that the capillaries mustbe produced with a very precise diameter. This requirement results inhigh costs. Another problem lies in the fact that the capillaries canclog, a state that leads to errors in the measurements. In addition, theinterior surface of the capillary has to be of the highest quality andtotally cleaned of foreign substances (e.g. grease), so that the bloodplatelets do not adhere, a state that would result in clogging orundesired effects on the flow. The outflow ends must be rounded so thatthe blood cells are not injured by shearing. In addition to the cost ofproduction that is increased hereby, expenses are incurred by therequisite quality controls. Handling the capillaries with such smalldimensions for further automatic processing is extremely difficult. Thecapillaries that result in the said drawbacks are, however, absolutelynecessary due to physiological reasons, because they simulate theresistance of the arterioles. The preceding capillaries make the processof hemostasis more effective, because, when the aperture is open, theshear of a large flow is limited at the start of the measuring processand in this manner the interaction between the thrombocytes and thecollagen is more effective.

Therefore, the object of the present invention is to provide a processand a device for the measurement of the aggregation of the bloodplatelets or the coagulation of the blood, in which process or withwhich device the problems attributable to the capillaries are avoided.

This problem is solved by a process with the features of patent claim 1and by a system with the features of patent claim 12.

The essential advantage of the invention lies in the fact that thecapillaries used in the prior art can be omitted, because thoseconditions, which are actually produced during the measurement with acapillary, are simulated by a volume flow/pressure control withoutcapillary. The present device for the measurement of the aggregration ofthe blood platelets or the coagulation of the blood is advantageouslysignificantly less expensive because the capillaries, which can beproduced only quite expensively in the prior art, are superfluous.

In the following the invention and its embodiments are explained indetail with reference to the figures.

FIG. 1 depicts a circuit diagram in order to explain the processaccording to the invention.

FIG. 2 depicts the dependence between the volume flow and the pressurein order to explain the process according to the invention.

FIG. 3 depicts the time-dependent pressure curve at the aperture.

FIG. 4 depicts a device according to the invention in order to carry outthe present process, and

FIGS. 5 and 6 depict other devices to carry out the present process.

FIG. 1 shows the equivalent circuit diagram of a known device with acapillary, as known, for example, from the DE 35 41 057 C2. The flowresistance R_(v) of the capillary, which is constant, is labelled 1.R_(A) denotes the flow resistance 2 of the aperture; I, the volume flow;and P, the pressure, generated by a pressure source 3. The volume flow Iis measured and displayed by a meter 4. At the flow resistance 2,representing the aperture, a drop in pressure ΔP is produced thatdepends on the clogging of the aperture or the thrombosis in the area ofthe same and rises starting from a minimum value (start of themeasurement at time to) up to the value P of the pressure source 3(clogging of the aperture), as shown in FIG. 3.

The volume flow quantity I is determined by the following equations:##EQU1## ΔP denotes the drop in pressure at the aperture. This equationyields the flow resistance 2 of the aperture according to the followingequation. ##EQU2##

Substituting R_(A) according to equation 3 into the equation 1 yieldsthe pressure P according to the following relation:

    P=ΔP+R.sub.v ·I                             (4)

From this the following equation for the volume flow I can be derived:##EQU3##

FIG. 2 shows the characteristic lines R_(v) and R_(A)(initial) as afunction of the pressure and the volume flow quantity. The functionsR_(A)(initial) and R_(v) intersect at a point 10, which is equivalent tothe working point just after the start of the measurement. At the startof the measurement the resistance R_(A)(initial) of the uncloggedaperture is known. It can be found by experiment on the basis of thedimensions of the aperture 2. Thus the characteristic line R_(A) isestablished. The characteristic line R_(v) follows from the dimensionsof the capillary to be simulated, where at a pressure of, for example,40 mm Hg the result is a volume flow of, for example, 150 μl/min. Thesecharacteristic lines are entered into a computer 50 (FIG. 4) and yieldthe intersecting point 10, which matches the conditions at the start ofthe measurement. When at this point the aperture 2 closes progressively,a corresponding rise in pressure ΔP can be detected. Then on the basisof the known characteristic line R_(v) the computer 50 adjusts thevolume flow I so far towards the bottom until I reaches a valuecorresponding to the characteristic line R_(v). This procedure isrepeated so often at specified time intervals until a specified volumeflow, e.g. the volume flow of the value 0, is reached, a state that isequivalent to complete clogging of the aperture 2.

Inversely one may also proceed in such a manner that the control holdsthe pressure constant during a period of time, and thereafter when thevolume flow has dropped by a specified amount, the pressure isreadjusted until the characteristic line R_(v) has been reached.

FIG. 3 shows, for example, that, starting from point 10, the pressure ΔPrises along the line 11 whereupon after a period of time dt the volumeflow I is reduced so far along the line 12 by actuating the piston 24 inFIG. 4 by means of the drive 26 under control of the computer 50 untilthe characteristic line R_(v) is reached again. After another rise inpressure ΔP (characteristic line 13) the volume flow is reduced againalong the line 14 after a time period dt until the characteristic lineR_(v) is reached. This is continued until finally the value P at thevolume flow quantity zero is reached.

When, for example, at a point 15 the pressure drops again along the line16 due to the partial dissolving of the clogging in the aperture 2, thevolume flow through the system is increased (line 17) until thecharacteristic line R_(v) is reached again.

Due to this described, continuous approaching of the characteristic lineR_(v) the conditions that would exist with the presence of a capillaryare accurately simulated in the present process.

At the start of the measurement the computer 50 can determine thecharacteristic line R_(A)(initial) of the aperture 2 by itself. Thistakes place in a first step in that at a constant volume flow thepressure drop is measured with the aperture open. This is then also ameasure for the blood viscosity.

According to FIG. 4, a first embodiment of the present device forcarrying out the process described above comprises a blood reservoir 20,to which, for example, blood can be conveyed by way of a feed opening21. At the same time the feed opening 21 is preferably closed by amembrane 30', which is penetrated by by the tip of the syringe in orderto feed blood from a syringe or the like. This opening serves then toventilate the chamber 30. Into the blood reservoir 20 the cylinder 22 ofa syringe 23 is introduced, in whose interior there is a piston 24,which can be moved in the longitudinal direction of the cylinder 22 withthe aid of a final control element 25, which can be actuated by a drive26 (arrow 31). A sealing between the cylinder 22 and the blood reservoir20 is accomplished with a seal 20'.

Into the bottom end of the cylinder 22, which is dipped into the bloodreservoir 20, a holder 27 can be tightly inserted with the aid of a seal29', the holder 27 exhibiting a passage opening 33, which empties on theside, facing the piston 24, into a recess 34, in which a part 28,exhibiting an aperture 29, is installed tightly in such a manner thatthe passage opening 33 precedes the aperture 29. Preferably the holder27 and the part 28, exhibiting the aperture 29, are designed as adisposable part in the form of a small unit that is easy to handle. Thisaccommodates the storage problems, which are caused by the relativelysmall refrigerators in the clinics. Between the part 28 with theaperture 29 and the piston 24 there is a chamber 30, which serves toreceive the blood issuing through the aperture 29. The pressure,prevailing in the chamber 30, is measured by a sensor 35, which is shownschematicly. The corresponding connecting line to the chamber 30 ismarked 36.

There is the possibility of bringing a specific liquid (e.g. NaCl orother substances) into the area of the aperture 29 by way of the line 37before a measurement is made, in order to saturate the part 28, madepreferably of a filter material (e.g. cellulose acetate). The liquid canbe fed into the chamber 30 by way of a line 37. The said lines 36, 37can run so as to be sealed through the piston 24 or the cylinder 22 tothe chamber 30.

Before making a measurement, care is taken that the blood from thereservoir 20 is drawn into the the passage 33 by moving the piston 24and thereafter through the aperture 29 into the chamber 30. The actualmeasurement can then start immediately or after a desired delay.

One important advantage of the embodiment of FIG. 4 lies in the factthat the measuring piston is coupled directly to the blood by way of thesmall air cushion of the chamber 30 without their being large reservoirsof air layered behind and interfering with the aperture 29, as in thecase of the prior art. The said coupling enables that the blood flowfollows without delay the movement of the piston; and thus thedisturbing wetting resistances between blood, aperture and e.g. NaCl canbe overcome immediately. Another feature, to keep the air chamber 30 assmall as possible, consists of filling the sensor 35 and at least onepart of the line 36 with preferably oil.

A rinsing liquid to rinse said chamber after making a measurement andbefore installing a new part 27 can be fed into the chamber 30 by way ofthe other line 37. In addition, air to dry the chamber 30 can beintroduced.

According to FIG. 5, a suction tube 45, preceding the aperture 29,projects into the blood reservoir 40. Preferably the tube extends intothe passage 33 and is tightly connected, preferably cemented (referencenumeral 27'), to the part 27. At the same time it must be pointed outthat the tube 45 does not generate any significant hydrodynamic pressureand cannot be compared with the capillaries of the prior art, which, ofcourse, the present invention is supposed to avoid. The tube 45, whichcan also be used in the embodiment of FIG. 4, also has another task,which is to represent the shear effects, from which the blood plateletssuffer as they slid along the inner circumference of the arterioles.These mechanical shear processes, which can be important for differentkinds of tests, can be simulated, in fact, only by providing thecorporeal tube 45.

Preferably the blood can be removed by way of the tube 45 from asocalled vacutainer tube, which is closed by a penetrable stopper andcontains the blood at subatmospheric pressure.

It must be pointed out that to simulate non-physiological processes theresistance of the capillary must be assumed to be nonlinear. It can alsofollow, for example, a quadratic function, according to which itincreases faster toward the end of the measurement than at the start.For example, high stroke pressures to simulate the socalled Willebrandfactor can play an important role during hemostatic processes.

Furthermore, it must be pointed out that, instead of the describedaspiration of the blood from a reservoir 20 into the aperture 29, saidblood can also be forced in the reversed direction from the cylinderchamber of the syringe 23 under pressure through the aperture.

Preferably the cylinder 22 and the blood reservoir 20 or 40 are made ofplastic. They and preferably the holder 27, exhibiting the part 28 withthe aperture 29, are designed together as a disposable part. At the sametime this throw-away part may or may not include the tube 45.Furthermore, it is conceivable to integrate the piston 24 and optionallyalso the final control element 25 into the disposable part.

If the cylinder 22 is made, for example, of glass and is not integratedinto the disposable part, it is rinsed automaticly together with theblood reservoir 20 or 40 after each measuring sequence. In this caseonly the holder 27 with the part 28 is designed as a throw-away part.

According to the schematic of FIG. 6, defined conditions are createdwhen the blood 101 is forced out of a reservoir 100 through an aperture108 in that the measurement is initiated only when the piston 104,pushing the blood, touches the surface of the blood 102. For thispurpose there is a sensor 120 that generates a signal, which indicatesthe level of the blood surface 102 and which actuates an actuator 121for the piston 104 in such a manner that said actuator moves the piston104 until it touches the blood surface 102.

What is claimed is:
 1. Process for the measurement of the aggregation ofblood platelets or the coagulation of blood, in which process the bloodflows through an aperture (29), containing a part (28), whereby theclogging of the aperture is measured, characterized in that the drop inpressure (ΔP) occurring during the clogging is measured at specific timeintervals (dt) at the aperture (29), and the volume flow (I) is changedin such a manner that it corresponds to a predetermined function, whichsimulates the flow resistance (R_(v)) of a capillary, preceding theaperture (29), or that during the predetermined time interval (dt) thepressure (ΔP) is held constant and thereafter, when the volume flow (I)has decreased by an amount, is readjusted until it matches the function.2. Process, as claimed in claim 1, characterized in that in a first stepthe resistance (R_(A)(initial)) of the aperture (29) is determined asthe function of the dimensions of the aperture (29); that from thedimensions of the capillary to be simulated the flow resistance (R_(v))is found; and that the measurement starts at a point (10), at which thecharacteristic lines (R_(A)(initial) and R_(v)) intersect.
 3. Process,as claimed in claim 1, characterized in that the blood is aspirated froma reservoir (20) directly into the aperture (29) with a piston/cylinderarrangement (23), which follows the aperture (29), into a chamber (30),preceding the piston (24) of the arrangement (23) in the cylinder (22)of the arrangement (23); that the pressure, prevailing in the chamber(30), is measured with a pressure sensor (35) and is entered into acomputer (50), in which the characteristic lines (R_(A)(initial) andR_(v)) are stored; and that to change the volume flow (I) the computer(50) moves with a drive the piston (24) in the cylinder (22) as afunction of the pressure drop ΔP, determined in the time interval (dt).4. Process, as claimed in claim 1, characterized in that a steppingmotor, which is coupled to the piston (24) by way of a final controlelement (25), is used as a drive (26).
 5. Process, as claimed in claim1, characterized in that a filter element, which contains the aperture(29), is used as the part (28).
 6. Process, as claimed in claim 5,characterized in that a cellulose acetate filter is used as the filterelement.
 7. Process, as claimed in claim 1, characterized in that thefilter element is wetted with a liquid before the measurement isinitiated and the blood is aspirated into the aperture (29).
 8. Process,as claimed in claim 7, characterized in that NaCl is used as the liquid.9. Process, as claimed in claim 1, characterized in that the aperture(29) is preceded by a tube (35), which does not generate any significanthydrodynamic pressure and by way of which the blood is aspirated fromthe reservoir (40) to the aperture (29), whereby the tube simulates thesliding of the particles of blood along the inner circumferences of thearterioles.
 10. Process, as claimed in claim 1, characterized in thatthe flow resistance (R_(v)) of the capillary is simulated by a linearcharacteristic line.
 11. Process, as claimed in claim 1, characterizedin that the flow resistance (R_(v)) of the capillary is simulated by anonlinear characteristic line.
 12. Process, as claimed in claim 1,characterized in that a piston (104), which can be moved by an actuator(121), forces the blood through the aperture (108) and that themeasurement is started when the piston (104) touches the blood surface(102), detected by a sensor (120).